Content deleted Content added
Ozzie10aaaa (talk | contribs) |
Citation bot (talk | contribs) Altered pmc. Add: bibcode, page, doi, authors 1-1. Removed URL that duplicated identifier. Removed parameters. Some additions/deletions were parameter name changes. Upgrade ISBN10 to 13. | Use this bot. Report bugs. | Suggested by Jay8g | Category:CS1 maint: PMC format | #UCB_Category 1/2 |
||
| (16 intermediate revisions by 6 users not shown) | |||
Line 5:
[[File:Antibody.svg|thumb|upright=1.2|Each antibody binds to a specific [[antigen]] in a highly specific interaction analogous to a lock and key.]]
An '''antibody''' ('''Ab''')
More narrowly, an ''antibody'' (''Ab'') can refer to the free (secreted) form of these proteins, as opposed to the membrane-bound form found in a [[B cell]] receptor. The term ''immunoglobulin'' can then refer to both forms. Since they are, broadly speaking, the same protein, the terms are often treated as synonymous.<ref name="Rhoades">{{cite book|url=https://archive.org/details/humanphysiologyw00rodn/page/584|title=Human Physiology|vauthors=Rhoades RA, Pflanzer RG|publisher=Thomson Learning|year=2002|isbn=978-0-534-42174-8|edition=5th|page=[https://archive.org/details/humanphysiologyw00rodn/page/584 584]|url-access=registration}}</ref>
To allow the immune system to recognize millions of different antigens, the antigen-binding sites at both tips of the antibody come in an equally wide variety. The rest of the antibody structure is relatively generic. In humans, antibodies occur in five classes, sometimes called isotypes: [[IgA]], [[IgD]], [[IgE]], [[IgG]], and [[IgM]]. Human IgG and IgA antibodies are also divided into discrete subclasses (IgG1, IgG2, IgG3, IgG4; IgA1 and IgA2). The class refers to the functions triggered by the antibody (also known as effector functions), in addition to some other structural features. Antibodies from different classes also differ in where they are released in the body and at what stage of an immune response. Importantly, while classes and subclasses of antibodies may be shared between species (at least in name), their functions and distribution throughout the body may be different. For example, mouse IgG1 is closer to human IgG2 than human IgG1 in terms of its function.▼
▲To allow the immune system to recognize millions of different antigens, the antigen-binding sites at both tips of the antibody come in an equally wide variety. The rest of the antibody structure is
The term [[humoral immunity]] is often treated as synonymous with the antibody response, describing the function of the immune system that exists in the body's humors (fluids) in the form of soluble proteins, as distinct from [[cell-mediated immunity]], which generally describes the responses of [[T cell]]s (especially cytotoxic T cells). In general, antibodies are considered part of the [[adaptive immune system]], though this classification can become complicated. For example, natural IgM,<ref>{{Cite journal |last1=Ehrenstein |first1=Michael R. |last2=Notley |first2=Clare A. |date=2010-10-15 |title=The importance of natural IgM: scavenger, protector and regulator |url=http://dx.doi.org/10.1038/nri2849 |journal=Nature Reviews Immunology |volume=10 |issue=11 |pages=778–786 |doi=10.1038/nri2849 |pmid=20948548 |s2cid=35784099 |issn=1474-1733}}</ref> which are made by B-1 lineage cells that have properties more similar to innate immune cells than adaptive, refers to IgM antibodies made independently of an immune response that demonstrate polyreactivity- they recognize multiple distinct (unrelated) antigens. These can work with the [[complement system]] in the earliest phases of an immune response to help facilitate clearance of the offending antigen and delivery of the resulting [[immune complex]]es to the [[lymph node]]s or [[spleen]] for initiation of an immune response. Hence in this capacity, the function of antibodies is more akin to that of innate immunity than adaptive. Nonetheless, in general antibodies are regarded as part of the adaptive immune system because they demonstrate exceptional specificity (with some exception), are produced through genetic rearrangements (rather than being encoded directly in [[germline]]), and are a manifestation of immunological memory.
In the course of an immune response, B cells can progressively [[Cellular differentiation|differentiate]] into antibody-secreting cells or into memory B cells.<ref>{{Cite journal |last1=Akkaya |first1=Munir |last2=Kwak |first2=Kihyuck |last3=Pierce |first3=Susan K. |date=April 2020 |title=B cell memory: building two walls of protection against pathogens |journal=Nature Reviews Immunology |language=en |volume=20 |issue=4 |pages=229–238 |doi=10.1038/s41577-019-0244-2 |pmid=31836872 |pmc=7223087 |issn=1474-1741}}</ref> Antibody-secreting cells comprise plasmablasts and [[plasma cell]]s, which differ mainly in the degree to which they secrete antibody, their lifespan, metabolic adaptations, and surface markers.<ref>{{Cite journal |last1=Tellier |first1=Julie |last2=Nutt |first2=Stephen L |date=2018-10-15 |title=Plasma cells: The programming of an antibody-secreting machine |url=http://dx.doi.org/10.1002/eji.201847517 |journal=European Journal of Immunology |volume=49 |issue=1 |pages=30–37 |doi=10.1002/eji.201847517 |pmid=30273443 |issn=0014-2980|hdl=11343/284565 |hdl-access=free }}</ref> Plasmablasts are rapidly proliferating, short-lived cells produced in the early phases of the immune response (classically described as arising extrafollicularly rather than from the [[germinal center]]) which have the potential to differentiate further into plasma cells.<ref>{{Citation |title=B Cell Memory and Plasma Cell Development |date=2015 |work=Molecular Biology of B Cells |pages=227–249 |url=https://linkinghub.elsevier.com/retrieve/pii/B978012397933900014X |access-date=2024-01-24 |publisher=Elsevier |language=en |doi=10.1016/b978-0-12-397933-9.00014-x |isbn=978-0-12-397933-9}}</ref> The literature is sloppy at times and often describes plasmablasts as just short-lived plasma cells- formally this is incorrect. Plasma cells, in contrast, do not divide (they are [[terminally differentiated]]), and rely on survival niches comprising specific cell types and cytokines to persist.<ref>{{Cite journal |last1=Chu |first1=Van T. |last2=Berek |first2=Claudia |date=2012-12-19 |title=The establishment of the plasma cell survival niche in the bone marrow |url=http://dx.doi.org/10.1111/imr.12011 |journal=Immunological Reviews |volume=251 |issue=1 |pages=177–188 |doi=10.1111/imr.12011 |pmid=23278749 |s2cid=205212187 |issn=0105-2896}}</ref> Plasma cells will secrete huge quantities of antibody regardless of whether or not their cognate antigen is present, ensuring that antibody levels to the antigen in question do not fall to 0, provided the plasma cell stays alive. The rate of antibody secretion, however, can be regulated, for example, by the presence of adjuvant molecules that stimulate the immune response such as [[Toll-like receptor|TLR]] ligands.<ref>{{Cite journal |last1=Dorner |first1=Marcus |last2=Brandt |first2=Simone |last3=Tinguely |first3=Marianne |last4=Zucol |first4=Franziska |last5=Bourquin |first5=Jean-Pierre |last6=Zauner |first6=Ludwig |last7=Berger |first7=Christoph |last8=Bernasconi |first8=Michele |last9=Speck |first9=Roberto F. |last10=Nadal |first10=David |date=2009-11-06 |title=Plasma cell toll-like receptor (TLR) expression differs from that of B cells, and plasma cell TLR triggering enhances immunoglobulin production |url=http://dx.doi.org/10.1111/j.1365-2567.2009.03143.x |journal=Immunology |volume=128 |issue=4 |pages=573–579 |doi=10.1111/j.1365-2567.2009.03143.x |pmid=19950420 |pmc=2792141 |issn=0019-2805}}</ref> Long-lived plasma cells can live for potentially the entire lifetime of the organism.<ref>{{Cite journal |last1=Joyner |first1=Chester J. |last2=Ley |first2=Ariel M. |last3=Nguyen |first3=Doan C. |last4=Ali |first4=Mohammad |last5=Corrado |first5=Alessia |last6=Tipton |first6=Christopher |last7=Scharer |first7=Christopher D. |last8=Mi |first8=Tian |last9=Woodruff |first9=Matthew C. |last10=Hom |first10=Jennifer |last11=Boss |first11=Jeremy M. |last12=Duan |first12=Meixue |last13=Gibson |first13=Greg |last14=Roberts |first14=Danielle |last15=Andrews |first15=Joel |date=March 2022 |title=Generation of human long-lived plasma cells by developmentally regulated epigenetic imprinting |journal=Life Science Alliance |volume=5 |issue=3 |pages=e202101285 |doi=10.26508/lsa.202101285 |issn=2575-1077 |pmc=8739272 |pmid=34952892}}</ref> Classically, the survival niches that house long-lived plasma cells reside in the bone marrow,<ref>{{Cite journal |last1=Halliley |first1=Jessica L. |last2=Tipton |first2=Christopher M. |last3=Liesveld |first3=Jane |last4=Rosenberg |first4=Alexander F. |last5=Darce |first5=Jaime |last6=Gregoretti |first6=Ivan V. |last7=Popova |first7=Lana |last8=Kaminiski |first8=Denise |last9=Fucile |first9=Christopher F. |last10=Albizua |first10=Igor |last11=Kyu |first11=Shuya |last12=Chiang |first12=Kuang-Yueh |last13=Bradley |first13=Kyle T. |last14=Burack |first14=Richard |last15=Slifka |first15=Mark |date=July 2015 |title=Long-Lived Plasma Cells Are Contained within the CD19−CD38hiCD138+ Subset in Human Bone Marrow |journal=Immunity |language=en |volume=43 |issue=1 |pages=132–145 |doi=10.1016/j.immuni.2015.06.016 |pmc=4680845 |pmid=26187412}}</ref> though it cannot be assumed that any given plasma cell in the bone marrow will be long-lived. However, other work indicates that survival niches can readily be established within the mucosal tissues- though the classes of antibodies involved show a different hierarchy from those in the bone marrow.<ref>{{Cite journal |last1=Tellier |first1=Julie |last2=Tarasova |first2=Ilariya |last3=Nie |first3=Junli |last4=Smillie |first4=Christopher S. |last5=Fedele |first5=Pasquale L. |last6=Cao |first6=Wang H. J. |last7=Groom |first7=Joanna R. |last8=Belz |first8=Gabrielle T. |last9=Bhattacharya |first9=Deepta |last10=Smyth |first10=Gordon K. |last11=Nutt |first11=Stephen L. |date=2024-01-03 |title=Unraveling the diversity and functions of tissue-resident plasma cells |url=http://dx.doi.org/10.1038/s41590-023-01712-w |journal=Nature Immunology |volume=25 |issue=2 |pages=330–342 |doi=10.1038/s41590-023-01712-w |pmid=38172260 |s2cid=266752931 |issn=1529-2908}}</ref><ref>{{Cite journal |last1=Landsverk |first1=Ole J. B. |last2=Snir |first2=Omri |last3=Casado |first3=Raquel Bartolomé |last4=Richter |first4=Lisa |last5=Mold |first5=Jeff E. |last6=Réu |first6=Pedro |last7=Horneland |first7=Rune |last8=Paulsen |first8=Vemund |last9=Yaqub |first9=Sheraz |last10=Aandahl |first10=Einar Martin |last11=Øyen |first11=Ole M. |last12=Thorarensen |first12=Hildur Sif |last13=Salehpour |first13=Mehran |last14=Possnert |first14=Göran |last15=Frisén |first15=Jonas |date=February 2017 |title=Antibody-secreting plasma cells persist for decades in human intestine |journal=The Journal of Experimental Medicine |volume=214 |issue=2 |pages=309–317 |doi=10.1084/jem.20161590 |issn=1540-9538 |pmc=5294861 |pmid=28104812}}</ref> B cells can also differentiate into memory B cells which can persist for decades similarly to long-lived plasma cells. These cells can be rapidly recalled in a secondary immune response, undergoing class switching, affinity maturation, and differentiating into antibody-secreting cells.
Antibodies are central to the immune protection elicited by most vaccines and infections (although other components of the immune system certainly participate and for some diseases are considerably more important than antibodies in generating an immune response, e.g. [[Shingles|herpes zoster]]).<ref>{{Cite journal |last=Plotkin |first=Stanley A. |date=2022 |title=Recent updates on correlates of vaccine-induced protection |journal=Frontiers in Immunology |volume=13 |pages=1081107 |doi=10.3389/fimmu.2022.1081107 |doi-access=free |issn=1664-3224 |pmc=9912984 |pmid=36776392}}</ref> Durable protection from infections caused by a given microbe – that is, the ability of the microbe to enter the body and begin to replicate (not necessarily to cause disease) – depends on sustained production of large quantities of antibodies, meaning that effective vaccines ideally elicit persistent high levels of antibody, which relies on long-lived plasma cells. At the same time, many microbes of medical importance have the ability to mutate to escape antibodies elicited by prior infections, and long-lived plasma cells cannot undergo affinity maturation or class switching. This is compensated for through memory B cells: novel variants of a microbe that still retain structural features of previously encountered antigens can elicit memory B cell responses that adapt to those changes. It has been suggested that long-lived plasma cells secrete B cell receptors with higher affinity than those on the surfaces of memory B cells, but findings are not entirely consistent on this point.<ref>{{Cite journal |last1=Sutton |first1=Henry J. |last2=Gao |first2=Xin |last3=Kelly |first3=Hannah G. |last4=Parker |first4=Brian J. |last5=Lofgren |first5=Mariah |last6=Dacon |first6=Cherrelle |last7=Chatterjee |first7=Deepyan |last8=Seder |first8=Robert A. |last9=Tan |first9=Joshua |last10=Idris |first10=Azza H. |last11=Neeman |first11=Teresa |last12=Cockburn |first12=Ian A. |date=2024-01-12 |title=Lack of affinity signature for germinal center cells that have initiated plasma cell differentiation |url=https://pubmed.ncbi.nlm.nih.gov/38228150 |journal=Immunity |volume=57 |issue=2 |pages=S1074–7613(23)00541–1 |doi=10.1016/j.immuni.2023.12.010 |issn=1097-4180 |pmid=38228150|pmc=10922795 |pmc-embargo-date=February 13, 2025 }}</ref>
Line 47 ⟶ 49:
These loops are referred to as the [[complementarity-determining region]]s (CDRs), since their shape complements that of an antigen.
Three CDRs from each of the heavy and light chains together form an antibody-binding site whose shape can be anything from a pocket to which a smaller antigen binds, to a larger surface, to a protrusion that sticks out into a groove in an antigen.
Typically
The existence of two identical antibody-binding sites allows antibody molecules to bind strongly to multivalent antigen (repeating sites such as [[polysaccharide]]s in [[bacterial cell wall]]s, or other sites at some distance apart), as well as to form antibody complexes and larger [[antigen-antibody complex]]es.<ref name="Janeway5"/>
Line 56 ⟶ 58:
and Nikoloudis et al.<ref name= Nikoloudis2014>{{cite journal | vauthors = Nikoloudis D, Pitts JE, Saldanha JW | title = A complete, multi-level conformational clustering of antibody complementarity-determining regions | journal = PeerJ | volume = 2 | issue = e456 | pages = e456 | year = 2014 | pmid = 25071986 | pmc = 4103072 | doi = 10.7717/peerj.456 | doi-access = free }}</ref> However, describing an antibody's binding site using only one single static structure limits the understanding and characterization of the antibody's function and properties. To improve antibody structure prediction and to take the strongly correlated CDR loop and interface movements into account, antibody paratopes should be described as interconverting states in solution with varying probabilities.<ref name="Fernandez-Quintero2021">{{cite journal | vauthors = Fernández-Quintero ML, Georges G, Varga JM, Liedl KR | title = Ensembles in solution as a new paradigm for antibody structure prediction and design | journal = mAbs | volume = 13 | issue = 1 | pages = 1923122 | year = 2021 | pmid = 34030577 | pmc = 8158028 | doi = 10.1080/19420862.2021.1923122 }}</ref>
In the framework of the [[immune network theory]], CDRs are also called idiotypes. According to immune network theory, the adaptive immune system is regulated by interactions between idiotypes. {{cn|date=July 2024}}
===Fc region===
Line 72 ⟶ 74:
Each [[immunoglobulin domain]] has a similar structure, characteristic of all the members of the [[immunoglobulin superfamily]]:
it is composed of between 7 (for constant domains) and 9 (for variable domains) [[β-strand]]s, forming two [[beta sheet]]s in a [[Beta sheet#Greek key motif|Greek key motif]].
The sheets create a "sandwich" shape, the [[immunoglobulin fold]], held together by a disulfide bond.{{cn|date=July 2024}}
===Antibody complexes===
Line 82 ⟶ 84:
Small antigens can cross-link two antibodies, also leading to the formation of antibody dimers, trimers, tetramers, etc.
Multivalent antigens (e.g., cells with multiple epitopes) can form larger complexes with antibodies.
An extreme example is the clumping, or [[Hemagglutination|agglutination]], of [[red blood cell]]s with antibodies in [[blood typing]] to determine [[blood group]]s: the large clumps become insoluble, leading to visually apparent [[precipitation (chemistry)|precipitation]].<ref>{{cite book |last1=Actor |first1=Jeffrey K. |title=Elsevier's Integrated Review Immunology and Microbiology |date=2012 |publisher=Elsevier |isbn=978-0-323-07447-6 |page=71 |edition=2nd |chapter=Immunoassays |doi=10.1016/B978-0-323-07447-6.00009-0 |chapter-url=https://doi.org/10.1016/B978-0-323-07447-6.00009-0 |quote=Antibody-antigen interactions: the basis of quantitative and qualitative assays. Experimentally, if a known concentration of antibody is mixed with increasing amounts of specific antigen, then cross-linked antibody-antigen complexes begin to precipitate from the solution.}}</ref><ref>{{cite web |title=Immunology Laboratory: Hemagglutination |url=http://www.medicine.mcgill.ca/physio/vlab/immun/hemag.htm |website=medicine.mcgill.ca |publisher=The McGill Physiology Virtual Lab |author=<!--Not stated--> |access-date=2024-08-29}}</ref><ref>{{cite journal |last1=Yeow |first1=Natasha |last2=Tabor |first2=Rico F. |last3=Garnier |first3=Gil |title=Mapping the distribution of specific antibody interaction forces on individual red blood cells |journal=Scientific Reports |date=3 February 2017 |volume=7 |issue=1 |page=41956 |doi=10.1038/srep41956 |pmid=28157207 |pmc=5291206 |bibcode=2017NatSR...741956Y }}</ref>
===B cell receptors===
Line 102 ⟶ 104:
|-
| [[IgA]] || 2
| style="text-align:left;" | Found in [[mucosal]] areas, such as the [[Gut (zoology)|gut]], [[respiratory tract]] and [[urogenital tract]], and prevents colonization by [[pathogen]]s.<ref>{{cite journal | vauthors = Underdown BJ, Schiff JM | title = Immunoglobulin A: strategic defense initiative at the mucosal surface | journal = Annual Review of Immunology | volume = 4 | issue = 1 | pages = 389–417 | year = 1986 | pmid = 3518747 | doi = 10.1146/annurev.iy.04.040186.002133 }}</ref> Also found in saliva, tears, and breast milk. Early clinical studies suggest that IgA isotype antibodies have potential as anti-cancer therapeutics, demonstrating the ability to reduce tumor growth.<ref name=":0">{{Cite journal |last1=Mark |first1=Jacqueline Kar Kei |last2=Lim |first2=Crystale Siew Ying |last3=Nordin |first3=Fazlina |last4=Tye |first4=Gee Jun |date=2022-11-01 |title=Expression of mammalian proteins for diagnostics and therapeutics: a review |journal=Molecular Biology Reports |language=en |volume=49 |issue=11 |pages=10593–10608 |doi=10.1007/s11033-022-07651-3 |issn=1573-4978 |pmc=9175168 |pmid=35674877}}</ref>
|-
| [[IgD]] || 1
| style="text-align:left;" | Functions mainly as an antigen receptor on B cells that have not been exposed to antigens.<ref name=Geisberger>{{cite journal | vauthors = Geisberger R, Lamers M, Achatz G | title = The riddle of the dual expression of IgM and IgD | journal = Immunology | volume = 118 | issue = 4 | pages = 429–37 | date = August 2006 | pmid = 16895553 | pmc = 1782314 | doi = 10.1111/j.1365-2567.2006.02386.x }}</ref> It has been shown to activate [[basophil]]s and [[mast cell]]s to produce [[antimicrobial]] factors.<ref name=Chen>{{cite journal | vauthors = Chen K, Xu W, Wilson M, He B, Miller NW, Bengtén E, Edholm ES, Santini PA, Rath P, Chiu A, Cattalini M, Litzman J, B Bussel J, Huang B, Meini A, Riesbeck K, Cunningham-Rundles C, Plebani A, Cerutti A | title = Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell-stimulating programs in basophils | journal = Nature Immunology | volume = 10 | issue = 8 | pages = 889–98 | date = August 2009 | pmid = 19561614 | pmc = 2785232 | doi = 10.1038/ni.1748 }}</ref> Besides, IgD has also been reported to induce the release of immunoactivity and pro-inflammatory mediators.<ref name=":0" />
|-
| [[IgE]] || 1
| style="text-align:left;" | IgE antibodies are the least abundant class of immunoglobulin, they can engage Fc receptors on monocytes and macrophages to activate various effector cell populations.<ref name=":0" />
Binds to [[allergen]]s and triggers [[histamine]] release from [[mast cell]]s and [[basophil]]s, and is involved in [[allergy]]. Humans and other animals evolved IgE to protect against [[parasitic worm]]s, though in the present, IgE is primarily related to allergies and asthma.<ref name="Pier">{{cite book |title=Immunology, Infection, and Immunity |vauthors=Pier GB, Lyczak JB, Wetzler LM |publisher=ASM Press |year=2004 |isbn=978-1-55581-246-1}}</ref> Although |-
| [[IgG]] || 4
| style="text-align:left;" | In its four forms, provides the majority of antibody-based immunity against invading pathogens.<ref name=Pier/> The only antibody capable of crossing the [[placenta]] to give passive immunity to the [[fetus]]. IgG is the most commonly used molecular format in current antibody drugs because it neutralizes infectious agents and activates the complement system to engage immune cells.<ref name=":0" />
|-
| [[IgM]]
| 1
| style="text-align:left;" | Expressed on the surface of B cells (monomer) and in a secreted form (pentamer) with very high [[avidity]]. Eliminates pathogens in the early stages of B cell-mediated (humoral) immunity before there is sufficient IgG.<ref name=Pier/><ref name=Geisberger/> IgM also is a pro-inflammatory antibody that serves as the primary defense and effectively stimulates the complement system with specialized immune functions, including higher avidity and steric hindrance, allowing it to neutralize viruses.<ref name=":0" />
|}
The antibody isotype of a B cell changes during cell [[Pre-pre B cell|development]] and activation. Immature B cells, which have never been exposed to an antigen, express only the IgM isotype in a cell surface bound form. The B lymphocyte, in this ready-to-respond form, is known as a "[[Naive B cell|naive B lymphocyte]]." The naive B lymphocyte expresses both surface IgM and IgD. The co-expression of both of these immunoglobulin isotypes renders the B cell ready to respond to antigen.<ref name=Goding>{{cite book | vauthors = Goding JW | title = Contemporary Topics in Immunobiology | chapter = Allotypes of IgM and IgD Receptors in the Mouse: A Probe for Lymphocyte Differentiation | volume = 8 | pages = 203–43 | date = 1978 | pmid = 357078 | doi = 10.1007/978-1-4684-0922-2_7 |isbn = 978-1-4684-0924-6}}</ref> B cell activation follows engagement of the cell-bound antibody molecule with an antigen, causing the cell to divide and [[Cellular differentiation|differentiate]] into an antibody-producing cell called a [[plasma cell]]. In this activated form, the B cell starts to produce antibody in a [[Secretion|secreted]] form rather than a [[cell membrane|membrane]]-bound form. Some [[daughter cell]]s of the activated B cells undergo [[isotype switching]], a mechanism that causes the production of antibodies to change from IgM or IgD to the other antibody isotypes, IgE, IgA, or IgG, that have defined roles in the immune system.{{cn|date=July 2024}}
===Light chain types===
{{Further|Immunoglobulin light chain}}
In mammals there are two types of [[immunoglobulin light chain]], which are called [[lambda]] (λ) and [[kappa]] (κ). However, there is no known functional difference between them, and both can occur with any of the five major types of heavy chains.<ref name=Janeway5/> Each antibody contains two identical light chains: both κ or both λ. Proportions of κ and λ types vary by species and can be used to detect abnormal proliferation of B cell clones. Other types of light chains, such as the [[iota]] (ι) chain, are found in other [[vertebrate]]s like sharks ([[Chondrichthyes]]) and bony fishes ([[Teleostei]]).{{cn|date=July 2024}}
===In non-mammalian animals===
Line 143 ⟶ 146:
==Antibody–antigen interactions==
The antibody's paratope interacts with the antigen's epitope. An antigen usually contains different epitopes along its surface arranged discontinuously, and dominant epitopes on a given antigen are called determinants.{{cn|date=July 2024}}
Antibody and antigen interact by spatial complementarity (lock and key). The molecular forces involved in the Fab-epitope interaction are weak and non-specific – for example [[Coulomb's law|electrostatic forces]], [[hydrogen bond]]s, [[hydrophobic interactions]], and [[van der Waals force]]s. This means binding between antibody and antigen is reversible, and the antibody's [[Affinity (pharmacology)|affinity]] towards an antigen is relative rather than absolute. Relatively weak binding also means it is possible for an antibody to [[Cross-reactivity|cross-react]] with different antigens of different relative affinities.{{cn|date=July 2024}}
== Function ==
Line 163 ⟶ 166:
}}]]
The main categories of antibody action include the following:{{cn|date=July 2024}}
* [[Neutralisation (immunology)|Neutralisation]], in which [[neutralizing antibody|neutralizing antibodies]] block parts of the surface of a bacterial cell or virion to render its attack ineffective
* [[Agglutination (biology)|Agglutination]], in which antibodies "glue together" foreign cells into clumps that are attractive targets for [[phagocytosis]]
Line 171 ⟶ 174:
** Encouragement of [[inflammation]] by [[chemotaxis|chemotactically]] attracting inflammatory cells
More indirectly, an antibody can signal immune cells to present antibody fragments to [[T cell]]s, or [[downregulate]] other immune cells to avoid [[autoimmunity]].{{cn|date=July 2024}}
Activated B cells [[cellular differentiation|differentiate]] into either antibody-producing cells called [[plasma cell]]s that secrete soluble antibody or [[memory B cell|memory cells]] that survive in the body for years afterward in order to allow the immune system to remember an antigen and respond faster upon future exposures.<ref name="pmid17337763">{{cite journal |vauthors=Borghesi L, Milcarek C |year=2006 |title=From B cell to plasma cell: regulation of V(D)J recombination and antibody secretion |journal=Immunologic Research |volume=36 |issue=1–3 |pages=27–32 |doi=10.1385/IR:36:1:27 |pmid=17337763 |s2cid=27041937 |doi-access=free}}</ref>
Line 188 ⟶ 191:
===Natural antibodies===
Humans and higher primates also produce "natural antibodies" that are present in serum before viral infection. Natural antibodies have been defined as antibodies that are produced without any previous infection, [[vaccination]], other foreign antigen exposure or [[passive immunization]]. These antibodies can activate the classical complement pathway leading to lysis of enveloped virus particles long before the adaptive immune response is activated. Antibodies are produced exclusively by B cells in response to antigens where initially, antibodies are formed as membrane-bound receptors, but upon activation by antigens and helper T cells, B cells differentiate to produce soluble antibodies.<ref name=":0" /> Many natural antibodies are directed against the disaccharide [[galactose]] α(1,3)-galactose (α-Gal), which is found as a terminal sugar on [[Glycosylation|glycosylated]] cell surface proteins, and generated in response to production of this sugar by bacteria contained in the human gut.<ref>{{cite news|author=Racaniello, Vincent |url=http://www.virology.ws/2009/10/06/natural-antibody-protects-against-viral-infection/ |date=6 October 2009 |title=Natural antibody protects against viral infection |website=Virology Blog |access-date=22 January 2010 |archive-url=https://web.archive.org/web/20100220015318/http://www.virology.ws/2009/10/06/natural-antibody-protects-against-viral-infection/ |archive-date=20 February 2010 |url-status=live}}</ref> These antibodies undergo quality checks in the endoplasmic reticulum (ER), which contains proteins that assist in proper folding and assembly. <ref name=":0" /> Rejection of [[Organ xenotransplantation|xenotransplantated organs]] is thought to be, in part, the result of natural antibodies circulating in the serum of the recipient binding to α-Gal antigens expressed on the donor tissue.<ref>{{cite journal | vauthors = Milland J, Sandrin MS | title = ABO blood group and related antigens, natural antibodies and transplantation | journal = Tissue Antigens | volume = 68 | issue = 6 | pages = 459–66 | date = December 2006 | pmid = 17176435 | doi = 10.1111/j.1399-0039.2006.00721.x }}</ref>
==Immunoglobulin diversity==
Line 200 ⟶ 203:
{{Further|V%28D%29J recombination}}
[[File:VDJ recombination.png|thumb|upright=1.25|Simplified overview of V(D)J recombination of immunoglobulin heavy chains]]
Somatic recombination of immunoglobulins, also known as ''V(D)J recombination'', involves the generation of a unique immunoglobulin variable region. The variable region of each immunoglobulin heavy or light chain is encoded in several pieces—known as gene segments (subgenes). These segments are called variable (V), diversity (D) and joining (J) segments.<ref name = namazee/> V, D and J segments are found in [[immunoglobulin heavy chain|Ig heavy chains]], but only V and J segments are found in [[Immunoglobulin light chain|Ig light chains]]. Multiple copies of the V, D and J gene segments exist, and are tandemly arranged in the [[genome]]s of [[mammal]]s. In the bone marrow, each developing B cell will assemble an immunoglobulin variable region by randomly selecting and combining one V, one D and one J gene segment (or one V and one J segment in the light chain). As there are multiple copies of each type of gene segment, and different combinations of gene segments can be used to generate each immunoglobulin variable region, this process generates a huge number of antibodies, each with different [[wikt:paratope|paratopes]], and thus different antigen specificities.<ref name="Market">{{cite journal | vauthors = Market E, Papavasiliou FN | title = V(D)J recombination and the evolution of the adaptive immune system | journal = PLOS Biology | volume = 1 | issue = 1 | pages = E16 | date = October 2003 | pmid = 14551913 | pmc = 212695 | doi = 10.1371/journal.pbio.0000016 | doi-access = free }}</ref> The rearrangement of several subgenes (i.e. V2 family) for lambda light chain immunoglobulin is coupled with the activation of microRNA miR-650, which further influences biology of B-cells.{{cn|date=July 2024}}
[[Recombination-activating gene|RAG]] proteins play an important role with V(D)J recombination in cutting DNA at a particular region.<ref name="Market"/> Without the presence of these proteins, V(D)J recombination would not occur.<ref name="Market"/>
Line 209 ⟶ 212:
{{Further|Somatic hypermutation|Affinity maturation}}
Following activation with antigen, B cells begin to [[Cell division|proliferate]] rapidly. In these rapidly dividing cells, the genes encoding the variable domains of the heavy and light chains undergo a high rate of [[point mutation]], by a process called ''somatic hypermutation'' (SHM). SHM results in approximately one [[nucleotide]] change per variable gene, per cell division.<ref name=diaz>{{cite journal | vauthors = Diaz M, Casali P | title = Somatic immunoglobulin hypermutation | journal = Current Opinion in Immunology | volume = 14 | issue = 2 | pages = 235–40 | date = April 2002 | pmid = 11869898 | pmc = 4621002 | doi = 10.1016/S0952-7915(02)00327-8 }}</ref> As a consequence, any daughter B cells will acquire slight [[amino acid]] differences in the variable domains of their antibody chains.{{cn|date=July 2024}}
This serves to increase the diversity of the antibody pool and impacts the antibody's antigen-binding [[Chemical affinity|affinity]].<ref>{{cite journal | vauthors = Honjo T, Habu S | title = Origin of immune diversity: genetic variation and selection | journal = Annual Review of Biochemistry | volume = 54 | issue = 1 | pages = 803–30 | year = 1985 | pmid = 3927822 | doi = 10.1146/annurev.bi.54.070185.004103 }}</ref> Some point mutations will result in the production of antibodies that have a weaker interaction (low affinity) with their antigen than the original antibody, and some mutations will generate antibodies with a stronger interaction (high affinity).<ref name=orguil>{{cite journal | vauthors = Or-Guil M, Wittenbrink N, Weiser AA, Schuchhardt J | title = Recirculation of germinal center B cells: a multilevel selection strategy for antibody maturation | journal = Immunological Reviews | volume = 216 | pages = 130–41 | date = April 2007 | pmid = 17367339 | doi = 10.1111/j.1600-065X.2007.00507.x | s2cid = 37636392 }}</ref> B cells that express high affinity antibodies on their surface will receive a strong survival signal during interactions with other cells, whereas those with low affinity antibodies will not, and will die by [[apoptosis]].<ref name=orguil/> Thus, B cells expressing antibodies with a higher affinity for the antigen will outcompete those with weaker affinities for function and survival allowing the average affinity of antibodies to increase over time. The process of generating antibodies with increased binding affinities is called ''affinity maturation''. Affinity maturation occurs in mature B cells after V(D)J recombination, and is dependent on help from [[helper T cell]]s.<ref>{{cite journal | vauthors = Neuberger MS, Ehrenstein MR, Rada C, Sale J, Batista FD, Williams G, Milstein C | title = Memory in the B-cell compartment: antibody affinity maturation | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 355 | issue = 1395 | pages = 357–60 | date = March 2000 | pmid = 10794054 | pmc = 1692737 | doi = 10.1098/rstb.2000.0573 }}</ref>
Line 221 ⟶ 224:
===Specificity designations===
{{anchor|valence}}An antibody can be called ''monospecific'' if it has specificity for a single antigen or epitope,<ref>[https://books.google.com/books?id=TfW5sUfeM5gC&pg=PA22 p. 22] in: {{Cite book | vauthors = Shoenfeld Y, Meroni PL, Gershwin ME | title = Autoantibodie | year = 2007 | publisher = Elsevier | location = Amsterdam; Boston | isbn = 978-0-444-52763-9 }}
</ref> or bispecific if it has affinity for two different antigens or two different epitopes on the same antigen.<ref>{{cite journal | vauthors = Spiess C, Zhai Q, Carter PJ | title = Alternative molecular formats and therapeutic applications for bispecific antibodies | journal = Molecular Immunology | volume = 67 | issue = 2 Pt A | pages = 95–106 | date = October 2015 | pmid = 25637431 | doi = 10.1016/j.molimm.2015.01.003 | doi-access = free }}</ref> A group of antibodies can be called ''polyvalent'' (or ''unspecific'') if they have affinity for various antigens<ref name=farlex-polyvalent/> or microorganisms.<ref name=farlex-polyvalent>[http://medical-dictionary.thefreedictionary.com/polyvalent Farlex dictionary > polyvalent] Citing: The American Heritage Medical Dictionary. 2004</ref> [[Intravenous immunoglobulin]], if not otherwise noted, consists of a variety of different IgG (polyclonal IgG). In contrast, [[monoclonal antibodies]] are identical antibodies produced by a single B cell.{{cn|date=July 2024}}
===Asymmetrical antibodies===
Heterodimeric antibodies, which are also asymmetrical antibodies, allow for greater flexibility and new formats for attaching a variety of drugs to the antibody arms. One of the general formats for a heterodimeric antibody is the "knobs-into-holes" format. This format is specific to the heavy chain part of the constant region in antibodies. The "knobs" part is engineered by replacing a small amino acid with a larger one. It fits into the "hole", which is engineered by replacing a large amino acid with a smaller one. What connects the "knobs" to the "holes" are the disulfide bonds between each chain. The "knobs-into-holes" shape facilitates antibody dependent cell mediated cytotoxicity. [[Single-chain variable fragment]]s ([[scFv]]) are connected to the variable domain of the heavy and light chain via a short linker peptide. The linker is rich in glycine, which gives it more flexibility, and serine/threonine, which gives it specificity. Two different scFv fragments can be connected together, via a hinge region, to the constant domain of the heavy chain or the constant domain of the light chain.<ref>{{cite journal | vauthors = Gunasekaran K, Pentony M, Shen M, Garrett L, Forte C, Woodward A, Ng SB, Born T, Retter M, Manchulenko K, Sweet H, Foltz IN, Wittekind M, Yan W | title = Enhancing antibody Fc heterodimer formation through electrostatic steering effects: applications to bispecific molecules and monovalent IgG | journal = The Journal of Biological Chemistry | volume = 285 | issue = 25 | pages = 19637–46 | date = June 2010 | pmid = 20400508 | pmc = 2885242 | doi = 10.1074/jbc.M110.117382 | doi-access = free }}</ref> This gives the antibody bispecificity, allowing for the binding specificities of two different antigens.<ref>{{cite journal | vauthors = Muller KM |title=The first constant domain (CH1 and CL) of an antibody used as heterodimerization domain for bispecific miniantibodies |journal=FEBS Letters |volume=422 |issue=2 |pages=259–264 |year=1998 | doi = 10.1016/s0014-5793(98)00021-0 |pmid=9490020 |s2cid=35243494 |doi-access=free |bibcode=1998FEBSL.422..259M }}</ref> The "knobs-into-holes" format enhances heterodimer formation but does not suppress homodimer formation.{{cn|date=July 2024}}
To further improve the function of heterodimeric antibodies, many scientists are looking towards artificial constructs. Artificial antibodies are largely diverse protein motifs that use the functional strategy of the antibody molecule, but are not limited by the loop and framework structural constraints of the natural antibody.<ref>{{cite journal | vauthors = Gao C, Mao S, Lo CH, Wirsching P, Lerner RA, Janda KD | title = Making artificial antibodies: a format for phage display of combinatorial heterodimeric arrays | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 11 | pages = 6025–30 | date = May 1999 | pmid = 10339535 | pmc = 26829 | doi = 10.1073/pnas.96.11.6025 | bibcode = 1999PNAS...96.6025G | doi-access = free }}</ref> Being able to control the combinational design of the sequence and three-dimensional space could transcend the natural design and allow for the attachment of different combinations of drugs to the arms.{{cn|date=July 2024}}
Heterodimeric antibodies have a greater range in shapes they can take and the drugs that are attached to the arms do not have to be the same on each arm, allowing for different combinations of drugs to be used in cancer treatment. Pharmaceuticals are able to produce highly functional bispecific, and even multispecific, antibodies. The degree to which they can function is impressive given that such a change of shape from the natural form should lead to decreased functionality.{{cn|date=July 2024}}
=== Interchromosomal DNA Transposition ===
Line 248 ⟶ 251:
==Medical applications==
===Disease diagnosis===
Detection of particular antibodies is a very common form of medical [[medical diagnosis|diagnostics]], and applications such as [[serology]] depend on these methods.<ref>{{cite web |url=http://www.immunospot.eu/elisa-animation.html |title=Animated depictions of how antibodies are used in ELISA assays |access-date=8 May 2007 |website=Cellular Technology Ltd.—Europe |archive-url=https://web.archive.org/web/20110614091640/http://www.elispot-analyzers.de/english/elisa-animation.html |archive-date=14 June 2011 |url-status=dead}}</ref> For example, in biochemical assays for disease diagnosis,<ref>{{cite web |url=http://www.immunospot.eu/elispot-animation.html |title=Animated depictions of how antibodies are used in ELISPOT assays |access-date=8 May 2007 |website=Cellular Technology Ltd.—Europe |archive-url=https://web.archive.org/web/20110516142529/http://www.elispot-analyzers.de/english/elispot-animation.html |archive-date=16 May 2011 |url-status=dead}}</ref> a [[titer]] of antibodies directed against [[Epstein-Barr virus]] or [[Lyme disease]] is estimated from the blood. If those antibodies are not present, either the person is not infected or the infection occurred a ''very'' long time ago, and the B cells generating these specific antibodies have naturally decayed.{{cn|date=July 2024}}
In [[clinical immunology]], levels of individual classes of immunoglobulins are measured by [[nephelometry]] (or [[turbidimetry]]) to characterize the antibody profile of patient.<ref>{{cite journal |author=Stern P |title=Current possibilities of turbidimetry and nephelometry |journal=Klin Biochem Metab |volume=14 |issue=3 |pages=146–151 |year=2006 |url=http://www.clsjep.cz/odkazy/kbm0603-146.pdf |archive-url=https://web.archive.org/web/20080410032918/http://www.clsjep.cz/odkazy/kbm0603-146.pdf |archive-date=10 April 2008 |url-status=dead}}</ref> Elevations in different classes of immunoglobulins are sometimes useful in determining the cause of [[liver]] damage in patients for whom the diagnosis is unclear.<ref name=Rhoades/> For example, elevated IgA indicates alcoholic [[cirrhosis]], elevated IgM indicates [[viral hepatitis]] and [[primary biliary cirrhosis]], while IgG is elevated in viral hepatitis, [[autoimmune hepatitis]] and cirrhosis.{{cn|date=July 2024}}
[[Autoimmune disorder]]s can often be traced to antibodies that bind the body's own [[epitope]]s; many can be detected through [[blood test]]s. Antibodies directed against [[red blood cell]] surface antigens in immune mediated [[hemolytic anemia]] are detected with the [[Coombs test]].<ref name=Dean>{{cite book | vauthors = Dean L |title= Blood Groups and Red Cell Antigens| year= 2005|publisher=National Library of Medicine (US) |location=NCBI Bethesda (MD)|chapter= Chapter 4: Hemolytic disease of the newborn |chapter-url= https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=rbcantigen.chapter.ch4}}</ref> The Coombs test is also used for antibody screening in [[blood transfusion]] preparation and also for antibody screening in [[antenatal]] women.<ref name=Dean/>
Practically, several immunodiagnostic methods based on detection of complex antigen-antibody are used to diagnose infectious diseases, for example [[ELISA]], [[immunofluorescence]], [[Western blot]], [[immunodiffusion]], [[immunoelectrophoresis]], and [[magnetic immunoassay]].<ref>{{cite journal |last1=Sullivan |first1=Mark V |last2=Stockburn |first2=William J |last3=Hawes |first3=Philippa C |last4=Mercer |first4=Tim |last5=Reddy |first5=Subrayal M |title=Green synthesis as a simple and rapid route to protein modified magnetic nanoparticles for use in the development of a fluorometric molecularly imprinted polymer-based assay for detection of myoglobin |journal=Nanotechnology |date=26 February 2021 |volume=32 |issue=9 |pages=095502 |doi=10.1088/1361-6528/abce2d|pmid=33242844 |bibcode=2021Nanot..32i5502S |doi-access=free |pmc=8314874 }}</ref> Antibodies raised against human [[chorion]]ic [[gonadotropin]] are used in over the counter pregnancy tests.{{cn|date=July 2024}}
New dioxaborolane chemistry enables radioactive [[fluoride]] ([[Fluorine-18|<sup>18</sup>F]]) labeling of antibodies, which allows for [[positron emission tomography]] (PET) imaging of [[cancer]].<ref>{{cite journal | vauthors = Rodriguez EA, Wang Y, Crisp JL, Vera DR, Tsien RY, Ting R | title = New Dioxaborolane Chemistry Enables [(18)F]-Positron-Emitting, Fluorescent [(18)F]-Multimodality Biomolecule Generation from the Solid Phase | language = EN | journal = Bioconjugate Chemistry | volume = 27 | issue = 5 | pages = 1390–1399 | date = May 2016 | pmid = 27064381 | pmc = 4916912 | doi = 10.1021/acs.bioconjchem.6b00164 }}</ref>
Line 277 ⟶ 280:
Antibodies used in research are some of the most powerful, yet most problematic reagents with a tremendous number of factors that must be controlled in any experiment including cross reactivity, or the antibody recognizing multiple epitopes and affinity, which can vary widely depending on experimental conditions such as pH, solvent, state of tissue etc. Multiple attempts have been made to improve both the way that researchers validate antibodies<ref>{{cite journal | vauthors = Saper CB | title = An open letter to our readers on the use of antibodies | journal = The Journal of Comparative Neurology | volume = 493 | issue = 4 | pages = 477–8 | date = December 2005 | pmid = 16304632 | doi = 10.1002/cne.20839 | s2cid = 14082678 | doi-access = free }}</ref><ref>{{Cite web|url=https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-011.html|title=NOT-OD-16-011: Implementing Rigor and Transparency in NIH & AHRQ Research Grant Applications|website=grants.nih.gov}}</ref> and ways in which they report on antibodies. Researchers using antibodies in their work need to record them correctly in order to allow their research to be reproducible (and therefore tested, and qualified by other researchers). Less than half of research antibodies referenced in academic papers can be easily identified.<ref>{{cite journal | vauthors = Vasilevsky NA, Brush MH, Paddock H, Ponting L, Tripathy SJ, Larocca GM, Haendel MA | title = On the reproducibility of science: unique identification of research resources in the biomedical literature | journal = PeerJ | volume = 1 | pages = e148 | date = 2 September 2013 | pmid = 24032093 | pmc = 3771067 | doi = 10.7717/peerj.148 | author-link7 = Melissa Haendel | doi-access = free }}</ref> Papers published in [[Faculty of 1000|F1000]] in 2014 and 2015 provide researchers with a guide for reporting research antibody use.<ref>{{cite journal | vauthors = Bandrowski A, Brush M, Grethe JS, Haendel MA, Kennedy DN, Hill S, Hof PR, Martone ME, Pols M, Tan S, Washington N, Zudilova-Seinstra E, Vasilevsky N | title = The Resource Identification Initiative: A cultural shift in publishing | journal = F1000Research | volume = 4 | pages = 134 | year = 2015 | pmid = 26594330 | pmc = 4648211 | doi = 10.12688/f1000research.6555.2 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Helsby MA, Fenn JR, Chalmers AD | title = Reporting research antibody use: how to increase experimental reproducibility | journal = F1000Research | volume = 2 | pages = 153 | date = 23 August 2013 | pmid = 24358895 | pmc = 3829129 | doi = 10.12688/f1000research.2-153.v2 | doi-access = free }}</ref> The RRID paper, is co-published in 4 journals that implemented the [[RRIDs]] Standard for research resource citation, which draws data from the antibodyregistry.org as the source of antibody identifiers<ref>{{Cite web|url=https://antibodyregistry.org/|title=The Antibody Registry|website=antibodyregistry.org}}</ref> (see also group at [[FORCE11|Force11]]<ref>{{cite web|title=Resource Identification Initiative|url=https://www.force11.org/group/resource-identification-initiative|website=FORCE11|access-date=18 April 2016|date=14 August 2013}}</ref>).
Antibody regions can be used to further biomedical research by acting as a guide for drugs to reach their target. Several application involve using bacterial plasmids to tag plasmids with the Fc region of the antibody such as [[pFUSE-Fc plasmid]].{{cn|date=July 2024}}
==Regulations==
Line 289 ⟶ 292:
===Before clinical trials===
* Product safety testing: Sterility ([[bacteria]] and [[Fungus|fungi]]), [[in vitro]] and [[in vivo]] testing for adventitious viruses, [[Murinae|murine]] [[retrovirus]] testing..., product safety data needed before the initiation of feasibility trials in serious or immediately life-threatening conditions, it serves to evaluate dangerous potential of the product.
* Feasibility testing: These are pilot studies whose objectives include, among others, early characterization of safety and initial proof of concept in a small specific patient population (in vitro or in vivo testing).{{cn|date=July 2024}}
===Preclinical studies===
* Testing [[cross-reactivity]] of antibody: to highlight unwanted interactions (toxicity) of antibodies with previously characterized tissues. This study can be performed in vitro (reactivity of the antibody or immunoconjugate should be determined with a quick-frozen adult tissues) or in vivo (with appropriates animal models).{{cn|date=July 2024}}
* [[Phases of clinical research|Preclinical]] [[pharmacology]] and [[toxicity]] testing: [[preclinical]] safety testing of antibody is designed to identify possible toxicity in humans, to estimate the likelihood and severity of potential adverse events in humans, and to identify a safe starting dose and dose escalation, when possible.
* Animal toxicity studies: [[Acute toxicity]] testing, repeat-dose toxicity testing, [[Chronic toxicity|long-term toxicity]] testing
| |||